The present invention relates to phosphonic acid derivatives having inhibitory activity against carboxypeptidase B, and to pharmaceutical compositions which comprise at least one of said derivative as an active ingredient and are useful for therapeutic and preventive treatment of various thrombosis, diseases caused by a vascular disorder, and organ disorders resulting from reduction of fibrinolysis.
Numbers of patients suffering from circulatory diseases have been increasing due to growth of aged population and changes in social circumstances. Among the aforementioned diseases, those caused by thrombus such as cerebral infarction and myocardial infarction show an increasing tendency. For these diseases, various antithrombotic treatments have been clinically applied.
The antithrombotic treatments are classified basically into anticoagulant, antiplatelet, and thrombolytic treatments. Among them, the thrombolytic treatments involve the lysis of formed thrombus, per se. In that sense, they are considered as more reasonable remedies for therapeutic treatment of thrombosis than the anticoagulant treatments, which prevent generation and development of secondary thrombus. At present, enzymatic agents such as urokinase and plasminogen activator have been clinically used as thrombolytic agents, and their clinical effectiveness has been recognized as one of therapeutic treatments for patients suffering from thrombosis.
Detailed mechanisms as to fibrinolysis have been being revealed with the progress of biochemical researches. A factor, which was reported as a fibrinogenolysis-inhibitory factor TAFI (thrombin activatable fibrinolysis inhibitor factor) activated by stimulation of coagulation, was revealed to be identical to plasma carboxypeptidase B (J. Biol. Chem. 14477(1995)). It was elucidated that plasma carboxypeptidase B inhibits fibrinolysis by interrupting plasminogen, which is a fibrinolytic enzyme mainly acting in the lysis of thrombus (fibrin), from binding to thrombi (J. Clin. Invest., 2534(1995)., J. Biol. Chem., 16603(1996), Thromb. Haemost., 829(1998), Circulation, 1328(1996)). Accordingly, plasma carboxypeptidase B inhibitors are expected to be used as agents for therapeutic and preventive treatments of various thromboses, which are antithrombotic agents based on enhancement of the lysis of thrombi.
As substances inhibiting pancreatic carboxypeptidase B, GEMSA (Biochemistry, 401(1978)., Arch. Biochem. Biophys., 487(1979)), SQ24798 (Biochemistry, 1427(1979)) and the like have been known so far.
Plasminogen activators and the like, which have been clinically used as thrombolytic agents at present, are not fully satisfactory from a clinical therapeutic viewpoint as their low safety such as hemorrhagic adverse effects and poor pharmacokinetics such as a short half-life, although their thrombolytic activities in an acute stage after thrombus formation are reliable.
In order to provide a thrombolytic agent having higher safety, the inventors of the present invention conducted researches to find a compound having inhibitory activity against plasma carboxypeptidase B. As a result, they found that phosphonic acid derivatives have potent inhibitory activity against carboxypeptidase B.
The present invention thus provide a compound represented by the following general formula (I) or a pharmacologically acceptable salt thereof, or a hydrate thereof or a solvate thereof: 
wherein R1 represents hydrogen atom, an alkyl group, a substituted alkyl group, an alkoxyl group, a substituted alkoxyl group, amino group, a substituted amino group, a carbocyclic group, a substituted carbocyclic group, a heterocyclic group, or a substituted heterocyclic group;
R2 and R3 may be the same or different and independently represent hydrogen atom, an alkyl group, a substituted alkyl group, an alkoxyl group, a substituted alkoxyl group, amino group, a substituted amino group, a carbocyclic group, a substituted carbocyclic group, a heterocyclic group, or a substituted heterocyclic group, or R2 and R3 may form a 5 to 7 membered carbon-ring together with the carbon atom to which they bind;
X represents xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, or xe2x80x94NHxe2x80x94;
A represents a group of the following formula (II): 
[in which R7 and R8 may be the same or different and independently represent hydrogen atom, an alkyl group, an acyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, carbamoyl group, a substituted carbamoyl group, or amidino group;
R9 and R10 may be the same or different and independently represent hydrogen atom, a halogen atom, hydroxyl group, phenyl group, an alkyl group, an alkoxyl group, an aryloxy group, an acyl group, carboxyl group, an alkoxycarbonyl group, carbamoyl group, a substituted carbamoyl group, amino group, a substituted amino group, nitro group, xe2x80x94SR11 group (R11 represents an alkyl group, phenyl group, or a substituted phenyl group), xe2x80x94SOR12 group (R12 represents an alkyl group, phenyl group, a substituted phenyl group, an alkoxyl group, an aryloxy group, amino group, or a substituted amino group), or xe2x80x94SO2R13 group (R13 represents an alkyl group, phenyl group, a substituted phenyl group, an alkoxyl group, an aryloxy group, amino group, or a substituted amino group);
m represents an integer of from 1 to 8; and
xe2x80x94(C)mxe2x80x94 represents a saturated or unsaturated carbon chain], or
A represents a group of the following formula (III): 
[in which R7 and R8 may be the same or different and independently represent hydrogen atom, an alkyl group, an acyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, carbamoyl group, a substituted carbamoyl group, or amidino group;
R24, R25, R26 and R27 may be the same or different and independently represent hydrogen atom, a halogen atom, hydroxyl group, an alkyl group, amino group, or a substituted amino group;
p and q independently represent an integer of from 0 to 2;
xe2x80x94(C)pxe2x80x94 and xe2x80x94(C)qxe2x80x94 independently represent single bond, or a saturated or unsaturated carbon chain; and
B represents a carbocyclic group, a substituted carbocyclic group, a heterocyclic group, or a substituted heterocyclic group], or
A represents a group of the following formula (TV): 
[in which R20 represents hydrogen atom, an alkyl group, an acyl group, an alkoxycarbonyl group, carbamoyl group, an alkylcarbamoyl group, or amidino group;
R28 and R29 may be the same or different and independently represent hydrogen atom, a halogen atom, hydroxyl group, an alkyl group, amino group, or an alkylamino group;
n and o independently represent an integer of from 0 to 5;
r represents an integer of from 0 to 4;
xe2x80x94(C)rxe2x80x94 independently represents single bond, or a saturated or unsaturated carbon chain; and
Y represents CH or nitrogen atom], or
A represents a group of the following formula (XIV): 
[in which R7 and R8 may be the same or different and independently represent hydrogen atom, an alkyl group, an acyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, carbamoyl group, a substituted carbamoyl group, or amidino group;
R30, R31, R32 and R33 may be the same or different and independently represent hydrogen atom, a halogen atom, hydroxyl group, an alkyl group, oxo group, amino group, or an alkylamino group;
s represents an integer of from 0 to 3;
t represents an integer of from 1 to 3;
xe2x80x94(C)sxe2x80x94 and xe2x80x94(C)txe2x80x94 independently represent single bond, or a saturated or unsaturated carbon chain; and
V represents xe2x80x94Oxe2x80x94 or xe2x80x94NHxe2x80x94]; and,
E represents hydrogen atom, or xe2x80x94CH2CH2xe2x80x94 to form together with A a piperidine ring group or a N-substituted piperidine ring group.
The present invention also provides a medicament which comprises as an active ingredient a substance selected from the group consisting of the compound represented by the aforementioned general formula (I) and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof. According to a preferred embodiment, there is provided the aforementioned medicament in the form of a pharmaceutical composition which comprises the aforementioned substance as an active ingredient together with a pharmacologically acceptable carrier. These medicaments are useful for therapeutic and/or preventive treatment of thrombotic diseases.
The present invention also provides an inhibitor against carboxypeptidase B which comprises as an active ingredient the substance selected from the group consisting of the compound represented by the aforementioned general formula (I) and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof.
The present invention further provides a use of the substance selected from the group consisting of the compound represented by the aforementioned general formula (I) and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof for the manufacture of the aforementioned medicament; and a method for therapeutic and/or preventive treatment of thrombotic diseases which comprises the step of administering to a mammal including a human a therapeutically and/or preventively effective amount of the substance selected from the group consisting of the compound represented by the aforementioned general formula (I) and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof.
In the specification, the alkyl group or an alkyl which constitutes a part of a substituent (e.g., alkoxyl groups) means a C1-10 alkyl group unless otherwise specifically mentioned, which encompasses straight chain alkyl groups including methyl group, ethyl group, n-propyl group, n-butyl group, n-pentyl group, n-hexyl group, n-heptyl group, n-octyl group and the like as typical examples; branched chain alkyl groups such as isopropyl group, s-butyl group, t-butyl group, 2-pentyl group, 3-pentyl group, and 1,1-dimethylpropyl group; cyclic alkyl groups such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, and cycloheptyl group; and alkyl groups as combinations of a straight or branched chain alkyl group and a cyclic alkyl group, such as cyclopropylmethyl group, cyclopropylethyl group, and cyclobutylmethyl group. In the groups containing an alkenyl moiety, the number of double bonds contained in the alkenyl moiety is not particularly limited. The alkenyl moiety may be any of a straight chain, a branched chain, cyclic moiety, or a combination thereof unless otherwise specifically mentioned, and is preferably straight chain or branched chain A double bond contained in the alkenyl moiety may be in either Z- or E-configuration.
In the specification, the acyl group or an acyl group which constitutes a part of a substituent means a functional group selected from the group consisting of formyl group, straight chain or branched chain C2-10 alkylcarbonyl groups, C7-15 aralkylcarbonyl groups, and C4-7 cycloalkycarbonyl groups. Examples include, for example, formyl group, acetyl group, propionyl group, butenyl group, benzoyl group, pivaloyl group and the like, and is preferably acetyl group.
The halogen atom means fluorine atom, chlorine atom, bromine atom, or iodine atom, and preferably fluorine atom or chlorine atom.
In the specification, the aryl group or an aryl group which constitutes a part of a substituent means, unless otherwise specifically mentioned, a 6 to 14-membered (monocyclic to tricyclic, preferably monocyclic or bicyclic) aromatic ring group such as phenyl, 1-naphthyl, 2-naphthyl, biphenyl, and 2-anthrylnaphthyl.
A heteroring means a 5 to 14-membered, preferably 5 to 10-membered, (monocyclic to tricyclic, preferably monocyclic or bicyclic) heteroring which contains 1 to 4, preferably 1 to 3, heteroatoms of 1 or 2 kinds selected from oxygen atom, nitrogen atom, and sulfur atom other than carbon atom. Examples include, for example, furan ring, pyrrole ring, pyrrolidine ring, pyrazole ring, imidazole ring, oxazole ring, thiazole ring, triazole ring, pyrane ring, pyridine ring, piperidine ring, dioxane ring, morpholine ring, pyridazine ring, pyrimidine ring, pyrazine ring, piperazine ring, triazine ring and the like, and preferably imidazole ring, triazole ring, pyridine ring, piperidine ring, pyrimidine ring, pyrazine ring, piperazine ring and the like. The heterocyclic group or a heterocyclic group which constitutes a part of the substituent means a residue of the aforementioned heteroring.
A carbon ring preferably means a saturated or unsaturated 5 to 7-membered ring. Examples include, for example, cyclopropane ring, cyclobutane ring, cyclopentane ring, cyclopentyl ring, cyclohexane ring, cycloheptane ring, benzene ring and the like.
When m represents an integer of 2 or more, the description: 
shows an alkylene group which consists of xe2x80x9cmxe2x80x9d groups of the methylene defined in the parenthesis bound to each other in a chain, and respective xe2x80x9cmxe2x80x9d groups of R9 and R10, each existing one to every xe2x80x9cmxe2x80x9d groups of the methylene, are independent and may be the same or different. The aforementioned description should not be interpreted as mere repetition of xe2x80x9cmxe2x80x9d groups of the same methylene. The other alkylene groups defined by p, q, r, s, or t are described in the same manner.
In formula (I), the alkyl group represented by R1, R2, or R3, or an alkyl group existing on the substituent represented by R1, R2, or R3 is preferably a C1-8 alkyl group, more preferably a C1-6 alkyl group, and further preferably a C1-4 alkyl group. When the alkyl group represented by R1, R2, or R3 is a cyclic alkyl group, the group may preferably be a C3-7 cycloalkyl group. Examples include, for example, cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl and the like.
One or more hydrogen atoms on the alkyl group represented by R1, R2, or R3 may be substituted. Examples of the substituent include hydroxyl group, phenyl group, a substituted phenyl group, a halogen atom, an alkoxyl group, a substituted alkoxyl group, an acyl group, carboxyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, carbamoyl group, a substituted carbamoyl group, amino group, a substituted amino group, nitro group, oxo group, a carbocyclic group, a substituted carbocyclic group, a heterocyclic group, a substituted heterocyclic group, xe2x80x94SR4 group (R4 represents an alkyl group, phenyl group, or a substituted phenyl group (examples of the substituent include a C1-4 alkyl group, a C1-4 alkoxyl groups and the like)), xe2x80x94SOR5 groups (R5 represents an alkyl group, phenyl group, a substituted phenyl group (examples of the substituent include a C1-4 alkyl group, a C1-4 alkoxyl group and the like), an alkoxyl group, amino group, or an alkylamino group), xe2x80x94SO2R6 group (R6 represents an alkyl group, phenyl group, a substituted phenyl group (examples of the substituent include a C1-4 alkyl group, a C1-4 alkoxyl group and the like), an alkoxyl group, amino group, or an alkylamino group) and the like. Preferred substituents include hydroxyl group, phenyl group, a substituted phenyl group (substituted with hydroxyl group, a halogen atom, an alkoxyl group, an amino group), a halogen atom, an alkoxyl group, an acyl group (e.g., acetyl group), carboxyl group, amino group, oxo group, and a heterocyclic group. The position of the substituent on the alkyl group is not particularly limited. When 2 or more substituents exist on the alkyl group, they may be the same or different.
In formula (I), the alkoxyl group represented by R1, R2, or R3, or an alkoxyl group existing on the substituent represented by R1, R2, or R3 is preferably a C1-8 alkoxyl group, more preferably a C1-6 alkoxyl group, and further preferably a C1-5 alkoxyl group.
One or more hydrogen atoms on the alkoxyl group represented by R1, R2, or R3 may be substituted. Examples of the substituent include hydroxyl group, phenyl group, a substituted phenyl group, a halogen atom, an alkoxyl group, a substituted alkoxyl group, an acyl group, carboxyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, carbamoyl group, a substituted carbamoyl group, amino group, a substituted amino group, xe2x80x94SR21 group (R21 represents an alkyl group, phenyl group, or a substituted phenyl group (examples of the substituent include a C1-4 alkyl group, a C1-4 alkoxyl group and the like)), xe2x80x94SOR22 group (R22 represents an alkyl group, phenyl group, a substituted phenyl group (examples of the substituent include a C1-4 alkyl group, a C1-4 alkoxyl group and the like), an alkoxyl group, amino group, or an alkylamino group), xe2x80x94SO2R23 group (R23 represents an alkyl group, phenyl group, a substituted phenyl group (examples of the substituent include a C1-4 alkyl group, a C1-4 alkoxyl group and the like), an alkoxyl group, amino group, or an alkylamino group) and the like. A preferred substituent includes phenyl group. The position of the substituent on the alkoxyl group is not particularly limited. When 2 or more substituents exist on the alkoxyl group, they may be the same or different.
In formula (I), one or two hydrogen atoms of the amino group represented by R1, R2, or R3 may be substituted. When two hydrogen atoms are substituted, the substituents may be the same or different. Examples of the substituent include an alkyl group, an alkenyl group, an acyl group, an acylalkyl group, an alkoxycarbonyl group, an alkoxycarbonylalkyl group, an arylalkyloxycarbonyl group, an alkylsulfonyl group, an alkylsulfonylalkyl group, an arylsulfonyl groups, an arylsulfonylalkyl group and the like. Examples of the substituted amino group include methylamino group, ethylamino group, n-propylamino group, isopropylamino group, allylamino group, phenylamino group, benzylamino group, cyclohexylamino group, dimethylamino group, allylmethylamino group, allylcyclohexylamino group, formylamino group, acetylamino group, benzoylamino group, pivaloylamino group, acetylmethylamino group, phthaloylamino group, methoxycarbonylamino group, isopropoxycarboonylamino group, methoxycarbonylmethylamino group, benzyloxycarbonylamino group, methylsulfonylamino group, phenylsulfonylamino group, benzenesulfonylamino group, and methyl(methylsulfonyl)amino group. Methylamino group, allylamino group, acetylamino group, methylsulfonylamino group, dimethylamino group, allylmethylamino group, or benzoylamino group is preferred.
In formula (I), the carbon ring represented by R1, R2, or R3, or the carbon ring represented by R2 and R3 together with the carbon atom to which they bind may be substituted with a halogen atom, an alkyl group, an alkoxyl group, oxo group, an acyl group, carbamoyl group, amino group, or a substituted amino group. A specific example includes 1-(3,5-dioxo)cyclohexyl group.
In formula (I), the heteroring represented by R1, R2, or R3 may be substituted with an alkyl group, an alkoxyl groups, oxo group, an acyl group, carbamoyl group, amino group, or a substituted amino group.
In formula (I), the group or atom represented by X is preferably oxygen atom.
In group (II), group (III), and group (XIV) represented by A in formula (I), examples of the group represented by R7 or R8 include hydrogen atom, an alkyl group, an acyl group, an alkoxycarbonyl group (e.g., methoxycarbonyl group, ethoxycarbonyl group, isopropoxycarbonyl group, t-butoxycarbonyl group and the like), an aryloxycarbonyl group (e.g., phenoxycarbonyl group and the like), carbamoyl group, an alkylcarbamoyl group (e.g., methylcarbamoyl group, ethylcarbamoyl group, N,N-dimethylcarbamoyl group, N,Nxe2x80x2-diethylcarbamoyl group and the like), an arylalkylcarbamoyl group (e.g., benzylcarbamoyl group and the like), and amidino group. Hydrogen atom, methyl group, ethyl group, formyl group, or amidino group is preferred, and hydrogen atom or methyl group is more preferred.
In group (II) represented by A in formula (I), examples of the group represented by R9 or R10 include hydrogen atom, a halogen atom, hydroxyl group, phenyl group, an alkyl group, an alkoxyl group, an aryloxy group (e.g., phenoxy group and the like), an acyl group, carboxyl group, an alkoxycarbonyl group (e.g., methoxycarbonyl group, isopropoxycarbonyl group and the like), carbamoyl group, an alkylcarbamoyl group (e.g., methylcarbamoyl group, N,N-dimethylcarbamoyl group, and the like), an alkenylcarbamoyl group (e.g., allylcarbamoyl group and the like), amino group, an alkylamino groups (e.g., methylamino group, ethylamino group, dimethylamino group and the like), an alkenylamino group (e.g., allylmethylamino group and the like), an acylamino group (e.g., acetylamino group, formylamino group, benzoylamino group and the like), an acylalkylamino group (e.g., acetylmethylamino group and the like), an alkoxycarbonylamino group (e.g., methoxycarbonylamino group and the like), nitro group, xe2x80x94SR11 group {R11 represents an alkyl group, phenyl group or a substituted phenyl group (examples of the substituent include C1-4 alkyl groups, C1-4 alkoxyl groups and the like)}, xe2x80x94SOR12 group {R12 represents an alkyl group, phenyl group, a substituted phenyl group (examples of the substituent include C1-4 alkyl groups, C1-4 alkoxyl groups and the like), an alkoxyl group (e.g., methoxy group, n-propoxy group and the like), an aryloxy group (e.g., phenoxy group and the like), amino group, or an alkylamino group (e.g., methylamino group, dimethylamino group and the like)}, and xe2x80x94SO2R13 group {R13 represents an alkyl group, phenyl group, a substituted phenyl group (examples of the substituent include a C1-4 alkyl group, a C1-4 alkoxyl group and the like), an alkoxyl group (e.g., methoxy group, n-propoxy group and the like), an aryloxy group (e.g., phenoxy group and the like), amino group, or an alkylamino group (e.g., methylamino group, dimethylamino group and the like)}. Hydrogen atom, fluorine atom, chlorine atom, methyl group, ethyl group, or acetyl group is preferred, and hydrogen atom is more preferred.
In group (II) represented by A in formula (I), the integer represented by m is preferably from 2 to 6, and more preferably 4 or 5.
In group (III) represented by A in formula (I), examples of the group represented by R24, R25, R26, or R27 include hydrogen atom, a halogen atom, hydroxyl group, an alkyl group, amino group, and a substituted amino group (examples of the substituent include C1-4 alkyl groups and the like).
In group (III) represented by A in formula (I), the carbon ring represented by B is preferably cyclohexane ring or benzene ring. One or more hydrogen atoms on the carbon ring represented by B may be substituted. Examples of the substituent include hydroxyl group, a halogen atom, phenyl group, an alkyl group, an alkoxyl group, an aryloxy group (e.g., phenoxy group and the like), an acyl group (e.g., formyl group, acetyl group, benzoyl group and the like), carboxyl group, an alkoxycarbonyl group, carbamoyl group, an alkylcarbamoyl group (e.g., methylcarbamoyl group, N,N-dimethylcarbamoyl group and the like), an alkenylcarbamoyl group (e.g., allylcarbamoyl group and the like), amino group, an alkylamino group (e.g., methylamino group, ethylamino group; dimethylamino group and the like), an alkenylamino group (e.g., allylmethylamino group and the like), an acylamino group (e.g., acetylamino group, formylamino group, benzoylamino group and the like), an acylalkylamino group (e.g., acetylmethylamino group and the like), an alkoxycarbonylamino group (e.g., methoxycarbonylamino group and the like), nitro group, xe2x80x94SR14 group {R14 represents an alkyl group, phenyl group, or a substituted phenyl group (examples of the substituent include a C1-4 alkyl group, a C1-4 alkoxyl group and the like)}, xe2x80x94SOR15 group {R15 represents an alkyl group, phenyl group, or a substituted phenyl group (examples of the substituent include a C1-4 alkyl group, a C1-4 alkoxyl group and the like), an alkoxyl group, amino group, or an alkylamino group (e.g., methylamino group, dimethylamino group and the like)} and xe2x80x94SO2R16 group {R16 represents an alkyl group, phenyl group, or a substituted phenyl group (examples of the substituent include a C1-4 alkyl group, a C1-4 alkoxyl group and the like), an alkoxyl group, amino group, or an alkylamino group (e.g., methylamino group, dimethylamino group and the like)}. Hydrogen atom, fluorine atom, chlorine atom, methyl group, ethyl group, acetyl group, carbamoyl group, carboxyl group, or nitro group is preferred.
In group (III) represented by A in formula (I), the heteroring represented by B is preferably imidazole ring, triazole ring, pyridine ring, piperidine ring, pyrimidine ring, pyrazine ring, or piperazine ring. One or more hydrogen atoms on the heteroring represented by B may be substituted. Examples of the substituent include hydroxyl group, a halogen atom, phenyl group, an alkyl group, an alkoxyl group, an aryloxy group (e.g., phenoxy group and the like), an acyl group (e.g., formyl group, acetyl group, benzoyl group and the like), carboxyl group, an alkoxycarbonyl group, carbamoyl group, an alkylcarbamoyl group (e.g., methylcarbamoyl group, N,N-dimethylcarbamoyl group and the like), an alkenylcarbamoyl group (e.g., allylcarbamoyl group and the like), amino group, an alkylamino group (e.g., methylamino group, ethylamino group, dimethylamino group and the like), an acylamino group (e.g., acetylamino group, formylamino group, benzoylamino group and the like), an acylalkylamino group (e.g., acetylmethylamino group and the like), an alkoxycarbonylamino group (e g., methoxycarbonylamino group and the like), nitro group, xe2x80x94SR17 group {R17 represents an alkyl group, phenyl group, or a substituted phenyl group (examples of the substituent include a C1-4 alkyl group, a C1-4 alkoxyl group and the like)}, xe2x80x94SOR18 group {R18 represents an alkyl group, phenyl group, a substituted phenyl group (examples of the substituent include a C1-4 alkyl group, a C1-4 alkoxyl group and the like.), an alkoxyl group, amino group, or an alkylamino group (e.g., methylamino group, dimethylamino group and the like)}, and xe2x80x94SO2R19 group {R19 represents an alkyl group, phenyl group, a substituted phenyl group (examples of the substituent include a C1-4 alkyl group, a C1-4 alkoxyl group and the like), an alkoxyl group, amino group, or an alkylamino group (e.g., methylamino group, dimethylamino group and the like)}. Hydrogen atom, fluorine atom, chlorine atom, methyl group, ethyl group, acetyl group, carbamoyl group, carboxyl group, or nitro group is preferred.
In group (IV) represented by A in formula (I), examples of the group represented by R20 include hydrogen atom, alkyl groups, acyl groups, alkoxycarbonyl groups, carbamoyl group, alkylcarbamoyl groups (e.g., methylcarbamoyl group and the like), and amidino group. Hydrogen atom or amidino group is preferred.
In group (IV) represented by A in formula (I), examples of the group represented by R28 or R29 include hydrogen atom, halogen atoms, hydroxyl group, alkyl groups, amino group, and alkylamino groups. Hydrogen atom is preferred.
In group (IV) represented by A in formula (I), the group or atom represented by Y is preferably CH.
In group (IV) represented by A in formula (I), the integer represented by n or o is preferably 2.
In group (IV) represented by A in formula (I), the integer represented by r is preferably 2.
In group (XIV) represented by A in formula (I), examples of the group represented by R30, R31, R32, or R33 include hydrogen atom, halogen atoms, hydroxyl group, alkyl groups, amino group, oxo group, alkylamino groups and the like. Hydrogen atom, an alkyl group, or oxo group is preferred.
In group (XIV) represented by A in formula (I), the group or atom represented by V is preferably xe2x80x94Oxe2x80x94.
In group (XIV) represented by A in formula (I), the integer represented by s or t is preferably 1 or 2.
In formula (I), examples of the N-substituent of the piperidine ring represented by E together with A include hydrogen atom, an alkyl group, a substituted alkyl group (examples of the substituent include hydroxyl group, a halogen atom, amino group, an alkylamino group, an acylamino group, an alkoxycarbonylamino group, carbamoylamino group, guanidino group, oxo group, amidino group and the like), an acyl group, and amidino group. Hydrogen atom, an aminoalkyl group, an aminoalkyl group having oxo group, or amidino group is preferred.
In formula (I), examples of the substituent of the substituted phenyl group, which may substitute on the alkyl group or the alkoxyl group represented by R1, R2 or R3, include hydroxyl group, a halogen atom, phenyl group, an alkyl group (e.g., a C1-4 alkyl group and the like), an alkoxyl group (e.g., a C1-4 alkoxyl group and the like), an acyl group (e.g., formyl group, acetyl group, propionyl group, butenyl group, benzoyl group, pivaloyl group and the like), carboxyl group, an alkoxycarbonyl group (e.g., a C1-4 alkoxycarbonyl group and the like), an arylalkyloxycarbonyl group (e.g., benzyloxycarbonyl group and the like), an aryloxycarbonyl group (phenoxycarbonyl group and the like), amino group, an alkylamino group (e.g., a C1-4 alkylamino group, dimethylamino group, cyclohexylamino group and the like), an alkenylamino group (e.g., allylamino group, allylmethylamino group, allylcyclohexylamino group and the like), an arylamino group (e.g., phenylamino group and the like), an arylalkylamino group (e.g., benzylamino group and the like), an acylamino group (e.g., formylamino group, acetylamino group, benzoylamino group, pivaloylamino group and the like), an acylalkylamino group (e.g., acetylmethylamino group, phthaloylamino group and the like), an alkoxycarbonylamino group (e.g., methoxycarbonylamino group, isopropoxycarbonylamino group and the like), an aryloxycarbonylamino group (e.g., benzyloxycarbonylamino group and the like), an alkoxycarbonylalkylamino group (e.g., methoxycarbonylmethylamino group and the like), an alkylsulfonylamino group (e.g., methylsulfonylamino group, methyl(methylsulfonyl)amino group and the like), an alkylsulfonylalkylamino group, an arylsulfonylamino group (e.g., benzenesulfonylamino group and the like), an arylsulfonylalkylamino group, carbamoyl group, an alkylcarbamoyl group (e.g., methylcarbamoyl group, ethylcarbamoyl group, N,N-dimethylcarbamoyl group, N,Nxe2x80x2-dimethylcarbamoyl group and the like), an arylalkylcarbamoyl group (e.g., benzylcarbamoyl group and the like), and nitro group. Hydroxyl group, a halogen atom, an alkoxyl group, or amino group is preferred.
In formula (I), an example of the substituent of the substituted alkoxyl group, which may substitute on the alkyl group or alkoxyl group represented by R1, R2, or R3, includes a C1-4 alkoxyl group. Methoxy group or isopropoxy group is preferred.
In formula (I), examples of the alkoxycarbonyl group or aryloxycarbonyl group, which may substitute on the alkyl group or the alkoxyl group represented by R1, R2, or R3, include a C2-5alkoxycarbonyl group, benzyloxycarbonyl group, and phenoxycarbonyl group. Methoxycarbonyl group or isopropoxycarbonyl group is preferred.
In formula (I), examples of the substituted carbamoyl group, which may substitute on the alkyl group or the alkoxyl group represented by R1, R2, or R3, include a N-(C1-4 alkyl)carbamoyl group, a N,N-di(C1-4 alkyl)carbamoyl group, and a N,Nxe2x80x2-di(C1-4 alkyl)carbamoyl group. Methylcarbamoyl group or N,N-dimethylcarbamoyl group is preferred.
In formula (I), examples of the substituted amino group, which may substitute on the alkyl group or the alkoxyl group represented by R1, R2, or R3, include an alkylamino group (e.g., methylamino group, ethylamino group, n-propylamino group, isopropylamino group, cyclohexylamino group, dimethylamino group and the like), an alkenylamino group (e.g., allylamino group, allylmethylamino group, allylcyclohexylamino group and the like), an arylamino group (e.g., phenylamino group and the like), an arylalkylamino group (e.g., benzylamino group and the like), an acylamino group (e.g., formylamino group, acetylamino group, benzoylamino group, pivaloylamino group, phthaloylamino group and the like), an acylalkylamino group (e.g., acetylmethylamino group and the like), an alkoxycarbonylamino group (e.g., methoxycarbonylamino group, isopropoxycarbonylamino group and the like), an alkoxycarbonylalkylamino group (e.g., methoxycarbonylmethylamino group and the like), an arylalkyloxycarbonyl group (e.g., benzyloxycarbonylamino group and the like), an alkylsulfonylamino group (e.g., methylsulfonylamino group, methyl(methylsulfonyl)amino group and the like), an alkylsulfonylalkylamino group, an arylsulfonylamino group (e.g., phenylsulfonylamino group and the like), and an arylsulfonylalkylamino group. Methylamino group, allylamino group, acetylamino group, or methylsulfonylamino group is preferred.
Among the compounds represented by general formula (I), preferred compounds include those wherein X is xe2x80x94Oxe2x80x94.
Other preferred compounds include those wherein A is group (II).
Other preferred compounds also include those wherein E is xe2x80x94CH2CH2xe2x80x94 that forms piperidine ring group or a N-substituted piperidine ring group together with A.
More preferred compounds are those wherein R1 is an alkyl group, a substituted alkyl group, an alkoxyl group, a substituted alkoxyl group, phenyl group, a substituted phenyl group, or a heterocyclic group, R2 and R3 may be the same or different and independently are hydrogen atom, an alkyl group, a substituted alkyl group, phenyl group, or a heterocyclic group, or R2 and R3 form a 5 to 7-membered carbon ring together with the carbon atom to which they bind, X is xe2x80x94Oxe2x80x94, A is group (II), and E is hydrogen atom, or E is xe2x80x94CH2CH2xe2x80x94 that forms piperidine ring group or a N-substituted piperidine ring group together with A.
Other class of more preferred compounds are those wherein R1 is an alkyl group, a substituted alkyl group, an alkoxyl group, a substituted alkoxyl group, phenyl group, a substituted phenyl group, or a heterocyclic group; R2 and R3 may be the same or different and are independently hydrogen atom, an alkyl group, a substituted alkyl group, phenyl group, or a heterocyclic group, or R2 and R3 form a 5 to 7-membered carbon ring together with the carbon atom to which they bind; X is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, or xe2x80x94NHxe2x80x94; A is
(a) group (II) in which R7 and R8 may be the same or different and are independently hydrogen atom, carbamoyl group, or amidino group; R9 and R10 may be the same or different and are independently hydrogen atom or an alkyl group; m is an integer of from 1 to 8; and xe2x80x94(C)mxe2x80x94 is a saturated carbon chain;
(b) group (III) in which both R7 and R8 are hydrogen atom; R24, R25, R26, and R27 may be the same or different and are independently hydrogen atom or an alkyl group; p and q are independently an integer of from 0 to 2; xe2x80x94(C)pxe2x80x94 and xe2x80x94(C)qxe2x80x94 are independently single bond or a saturated carbon chain; and B is a carbocyclic group;
(c) group (IV) in which R20 is hydrogen atom; R28 and R29 may be the same or different and are independently hydrogen atom or an alkyl group; n and o are independently an integer of from 0 to 5; r is independently an integer of from 0 to 4; xe2x80x94(C)rxe2x80x94 is independently single bond or a saturated carbon chain; and Y is CH; or
(d) group (XIV) in which both R7 and R8 are hydrogen atom; R30, R31, R32, and R33 may be the same or different and are independently hydrogen atom, an alkyl group, or oxo group; s is an integer of from 0 to 3; t is an integer of 1 to 3; xe2x80x94(C)sxe2x80x94 and xe2x80x94(C)txe2x80x94 are independently single bond or a saturated carbon chain; and V is xe2x80x94Oxe2x80x94; and E is hydrogen atom, or E is xe2x80x94CH2CH2xe2x80x94 that forms piperidine ring group or a N-substituted piperidine ring group together with A.
Further preferred compounds include those wherein R1 is an alkyl group, a substituted alkyl group, an alkoxyl group, a substituted alkoxyl group, phenyl group, a substituted phenyl group, or a heterocyclic group; R2 and R3 may be the same or different and are independently hydrogen atom, an alkyl group, a substituted alkyl group, phenyl group, or a heterocyclic group, or R2 and R3 form a 5 to 7-membered carbon ring together with the carbon atom to which they bind; X is xe2x80x94Oxe2x80x94; A is:
(a) group (II) in which R7 and R8 may be the same or different and are independently hydrogen atom, carbamoyl group, or amidino group; R9 and R10 may be the same or different and are independently hydrogen atom or an alkyl group; m is an integer of from 1 to 8; and xe2x80x94(C)mxe2x80x94 is a saturated carbon chain; or
(b) group (XIV) in which both R7 and R8 are hydrogen atom; R30, R31, R32, and R33 may be the same or different and are independently hydrogen atom, an alkyl group, or oxo group; s is an integer of from 0 to 3; t is an integer of from 1 to 3; xe2x80x94(C)sxe2x80x94 and xe2x80x94(C)txe2x80x94 are independently single bond or a saturated carbon chain; and V is xe2x80x94Oxe2x80x94; and E is hydrogen atom, or E is xe2x80x94CH2CH2xe2x80x94 that forms piperidine ring group or a N-substituted piperidine ring group together with A.
Still further preferred compounds include those wherein R1 is an alkyl group or a phenylalkyl group; R2 and R3 may be the same or different and are independently an alkyl group; X is xe2x80x94Oxe2x80x94; A is group (II) in which R7 and R8 may be the same or different and are independently hydrogen atom, carbamoyl group, or amidino group; R9 and R10 may be the same or different and are independently hydrogen atom or an alkyl group;
m is an integer of from 1 to 8; and xe2x80x94(C)mxe2x80x94 is a saturated carbon chain; and E is hydrogen atom.
Preferred specific examples of the compound represented by general formula (I) include, but not limited thereto:
(S)-6-amino-2-(((R)-1-(benzyloxycarbonylamino)ethyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((2-ethyl-1-(3-phenylpropanoylamino)butyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((1-(3-phenylpropanoylamino)ethyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-(((3-phenylpropanoylamino)methyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((cyclopropyl(3-phenylpropanoylamino)methyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-5-amino-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)pentanoic acid,
(S)-6-amino-2-((1-(3-phenylpropanoylamino)butyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((1-cyclohexyl-1-(3-phenylpropanoylamino)methyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((1-cyclobutyl-1-(3-phenylpropanoylamino)methyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-4-amino-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)butanoic acid,
(S)-6-amino-2-((3-methyl-1-(3-phenylpropanoylamino)butyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)-4-ureido-butanoic acid,
(S)-6-amino-2-((1-(3-phenylpropanoylamino)cyclohexyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)-5-ureido-pentanoic acid,
(S)-6-amino-2-((1-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-4-guanidino-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)butanoic acid,
(S)-5-guanidino-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)pentanoic acid,
(S)-6-amino-2-((2-methyl-(1R)-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((1-(3-phenylpropanoylamino)cyclopentyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((2-methyl-(1S)-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
6-amino-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)hydroxyphosphinoyl)methylhexanoic acid,
(S)-6-amino-2-((3,3-dimethyl-1-(3-phenylpropanoylamino)butyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-(2-methyl-1-(4-phenylbutanoylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((4,4,4-trifluoro-1-(3-phenylpropanoylamino)butyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-7-amino-2-((1-(3-phenylpropanoylamino)cyclopentyl)(hydroxyphosphinoyl)oxy)heptanoic acid,
(R)-7-amino-2-((1-(3-phenylpropanoylamino)cyclopentyl)(hydroxyphosphinoyl)oxy)heptanoic acid,
(S)-7-amino-2-((2-methyl-(1R)-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)heptanoic acid,
2-(2-methyl-(1R)-(3-phenylpropanoylamino)propyl(hydroxyphosphinoyl)oxy)-4-(piperidin-4-yl)butanoic acid,
1-(trans-(4-aminomethylcyclohexyl))-1-(2-methyl-(1R)-(3-phenylpropanoylamino)propyl(hydroxyphosphinoyl)oxy)acetic acid,
3-aminoacetoxy-2-(2-methyl-(1R)-(3-phenylpropanoylamino)propyl(hydroxyphosphinoyl)oxy)propanoic acid,
8-amino-2-(2-methyl-(1R)-(3-phenylpropanoylamino)propyl(hydroxyphosphinoyl)oxy)octanoic acid,
(S)-6-amino-2-((1-phenyl-1-(3-phenylpropanoylamino)methyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((1-(3-phenylpropanoylamino)-1-(tetrahydropyran-4-yl)methyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-5-amino-2-((3-methyl-1-(3-phenylpropanoylamino)butyl)(hydroxyphosphinoyl)oxy)pentanoic acid,
(S)-6-amino-2-((2-hydroxy-1-(3-phenylpropanoylamino)ethyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((1-cycloheptyl-1-(3-phenylpropanoylamino)methyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((1-(piperidin-4-yl)-1-(3-phenylpropanoylamino)methyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((4-amino-1-(3-phenylpropanoylamino)butyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((1-(4-methylcyclohexyl)-1-(3-phenylpropanoylamino)methyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-(((1R)-((2S)-amino-3-phenylpropanoylamino)-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((2-methyl-(1R)-phenylacetylaminopropyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((1-((2R)-amino-3-phenylpropanoylamino)-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((1-(3-cyclopentylpropanoylamino)-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((1-(2,4-difluorobenzoylamino)-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((1-benzoylamino-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((1-(3-(2-methoxyphenyl)propanoylamino)-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((1-(4-methoxyphenyl)acetylamino-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((1-heptanoylamino-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((1-(2-amino-2-phenylacetylamino)-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((2-methyl-1-((pyridin-2-yl)acetylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((1-(4-methoxybenzoylamino)-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-(((1R)-(4-methoxybenzoylamino)-2-methylpropyl)(hydroxyphosphinoyl) oxy)hexanoic acid,
(S)-6-amino-2-((1-dodecanoylamino-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-2-((1-acetylamino-2-methylpropyl)(hydroxyphosphinoyl)oxy)-6-aminohexanoic acid,
(S)-6-amino-2-((1-(3-(4-aminophenyl)propanoylamino)-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((1-(3-(3-aminophenyl)propanoylamino)-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((2-methyl-1-(trifluoroacetylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((2-methyl-1-(3-phenyl-(2S)-(3-phenylpropanoylamino)propanoylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((2-methyl-1-(5-oxohexanoylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((1-((3R)-hydroxybutanoylamino)-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((1-(3-methoxypropanoylamino)-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((2-methyl-1-(3,4,5-trimethoxybenzoylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((1-(3-carboxypropanoylamino)-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((2-methyl-1-(pyridin-2-carbonylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((2-methyl-1-(morpholine-4-carbonylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
4-((2-methyl-1-(3-phenylpropionylamino)propyl)(hydroxyphosphinoyl)oxy)piperidine-4-carboxylic acid,
1-amidino-4-((2-methyl-1-(3-phenylpropionylamino)propyl)(hydroxyphosphinoyl)oxy)piperidine-4-carboxylic acid,
1-(2-aminoethyl)-4-((2-methyl-1-(3-phenylpropionylamino)propyl)(hydroxyphosphinoyl)oxy)piperidine-4-carboxylic acid,
(R)-6-amino-2-((2-methyl-(1R)-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoic acid, and
7-amino-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)hydroxyphosphinoyl)methylheptanoic acid.
The compound represented by the aforementioned formula (I) may optionally have one or more asymmetric carbon atoms and exist as a stereoisomer (an optical isomer or a diastereoisomer) based on the asymmetric carbon atom(s). Any mixtures of the stereoisomers and racemates as well as the stereoisomers in a pure form fall within the scope of the present invention, and any of the aforementioned substances may be used as an active ingredient of the medicament of the present invention. When the compound represented by the aforementioned formula (I) has an olefinic double bond, the compound may exist as a geometrical isomer in either Z- or E-form or a mixture thereof, any of which falls within the scope of the present invention. The geometrical isomer in a pure form or a mixture thereof may be used as an active ingredient of the medicament of the present invention.
Among the compounds of formula (I) according to the present invention, those wherein X is oxygen atom or xe2x80x94NHxe2x80x94 in formula (I) can be prepared by synthetic method (I), (II), or (III) shown below. The compounds wherein X is xe2x80x94CH2xe2x80x94 and E is hydrogen atom can be prepared by the following synthetic method (IV), (V), (VI), or (VII). The compounds wherein X is xe2x80x94CH2xe2x80x94 and E is xe2x80x94CH2CH2xe2x80x94 that forms a piperidine ring group or a N-substituted piperidine ring group together with A can be prepared by synthetic method (VI) or (VII). However, preparations of the compounds of the present invention are not limited to these methods.
In order to synthesize the compound of formula (I) of the present invention, the amino group (the amino group herein defined includes an amino group on the piperidine ring formed by E together with A.), imino group, and carboxyl group used in the following synthetic methods (I) to (VII) may be protected, if desired. As a protecting group, ordinary protecting groups can be used. Preferably, examples for an amino group or an imino group includes methoxycarbonyl group, tert-butyloxycarbonyl group, benzyloxycarbonyl group, methoxybenzyloxycarbonyl group, nitrobenzyloxycarbonyl group, allylbenzyloxycarbonyl group, acetyl group, trifluoroacetyl group, trichloroacetyl group, benzoyl group, phthaloyl group, trityl group, benzyl group, methoxybenzyl group, allyl group, formyl group and the like, and examples for carboxyl group include methyl group, tert-butyl group, benzyl group, paramethoxybenzyl group, nitrobenzyl group, allyl group, benzhydryl group, trityl group and the like.
Synthetic Method (I) 
[In the scheme, R1, R2, R3, A, and E have the same meanings as those defined in formula (I), W represents oxygen atom or xe2x80x94NHxe2x80x94, and Z represents hydrogen atom, hydroxyl group, or alkoxyl group.]
A compound of the formula (VII) can be prepared according to the method described in Tetrahedron Lett., 7333 (1991), U.S. Pat. No. 4,616,005 or the like. Specifically, the method comprises condensing a compound of formula (V) and a compound of formula (VI) by applying, for example, the dehydration method using N,Nxe2x80x2-dicyclohexylcarbodiimide (DCC), benzotriazoleoxytrisdimethylaminophosphonium tetrafluorophosphate (BOP) or the like, the acid halide method using thionyl chloride, oxalyl chloride, phosphorus oxychloride or the like, the mixed acid anhydride method using pivaloyl chloride, a chloroformic acid ester or the like in a solvent which does not participate in the reaction for a reaction time of from 0.5 to 72 hours, preferably from 2 to 24 hours at a reaction temperature of from xe2x88x9278xc2x0 C. to 100xc2x0 C., preferably from 0xc2x0 C. to 30xc2x0 C.
As the amine of formula (VI), a commercially available compound may be used, or the amine can be synthesized according to the method described in Synthesis, 370(1998), Liebigs. Ann. Chem., 861(1988), J. Chem. Soc. Perkin trans. 1, 2845(1984) or the like. Where Z is hydrogen atom in the compound of formula (VII), the hydrogen atom can be converted into hydroxyl group by an ordinary oxidation in this step, and the hydroxyl group may be converted into an alkoxyl group, if desired.
The condensation between the compound of formula (VII) and a carboxylic acid compound of formula (VIII) can be carried out according to the method described in J. Am. Chem. Soc., 297(1991), J. Org. Chem., 658(1994), J. Med. Chem., 3303(1998), Synthesis, 556(1986), J. Med. Chem., 1459(1990), Tetrahedron Lett., 1751(1986) or the like. Specifically, the method comprises condensing the compound of formula (VII) and the compound of formula (VIII) by applying, for example, the dehydration method using N-(dimethylaminopropyl)-Nxe2x80x2-ethylcarbodiimide hydrochloride, N,Nxe2x80x2-dicyclohexylcarbodiimide (DCC), benzotriazoleoxytrisdimethylaminophosphonium tetrafluorophosphate (BOP) or the like, the acid halide method using thionyl chloride, oxalyl chloride, phosphorus oxychloride or the like, the mixed acid anhydride method using pivaloyl chloride, a chloroformic acid ester or the like in a solvent which does not participate in the reaction for a reaction time of from 0.5 to 72 hours, preferably from 2 to 24 hours at a reaction temperature of from xe2x88x9278xc2x0 C. to 100xc2x0 C., preferably from 0xc2x0 C. to 30xc2x0 C. The compound wherein X is oxygen atom or xe2x80x94NHxe2x80x94 in formula (I) can be synthesized through deprotection at need after the condensation, or when Z is hydrogen atom, by performing oxidation according to a conventional method after the condensation, and then deprotection at need.
Synthetic Method (II) 
[In the scheme, R1, R2, R3, A, E, W, and Z have the same meanings as those defined above.]
The compound of formula (I) can be synthesized according to the method shown in the aforementioned synthetic method (I).
Where Z is hydrogen atom in a compound of formula (IX), the hydrogen atom can be converted into hydroxyl group by an ordinary oxidation in this step, and the resulting hydroxyl group may be converted into an alkoxyl group, if desired.
The condensation between the compound of formula (V) and the compound of formula (IX) can be performed in the same manner as those described in the aforementioned synthetic method (I). The compound wherein X is oxygen atom or xe2x80x94NHxe2x80x94 in formula (I) can be synthesized through deprotection at need after the condensation, or where Z is hydrogen atom, by an oxidation in a conventional manner after the condensation, and then deprotection at need.
Synthetic Method (III) 
[In the scheme, R1, R2, R3, A, E, W, and Z have the same meanings as those defined above.]
A compound of formula (X) can be prepared according to the method described in Tetrahedron Lett., 5457(1996), Ibid., 6073(1996) or the like. Specifically, the compound of formula (X) wherein Z is hydroxyl group or an alkoxyl group can be obtained by reacting a compound of formula (VIII) with a phosphorylating agent such as 2-chloro-4H-1,3,2-benzodioxaphophorin-4-one, 2-chloro-1,3,2-dioxaphophorane, 2-cyanoethyl N,Nxe2x80x2-diisopropylchlorophosphoramidate, and phosphorus trichloride in a solvent which does not participate in the reaction for a reaction time of from 0.5 to 72 hours, preferably from 2 to 24 hours, at a reaction temperature of from xe2x88x9278xc2x0 C. to 100xc2x0 C., preferably from xe2x88x9230xc2x0 C. to 30xc2x0 C., and then performing hydrolysis or alcoholysis, if desired. When Z is hydroxyl group in formula (X), a compound wherein Z is an alkoxyl group in formula (X) can also be obtained by performing esterification by a conventional method.
A compound of formula (IX) can be synthesized according to the method described in Tetrahedron Lett., 5457(1996) or the like. Specifically, the compound of formula (IX) wherein Z is hydroxyl group or an alkoxyl group can be obtained by reacting the compound of formula (X) with the compound of formula (XI), per se, or under irradiation by ultrasound or in the presence of a Lewis acid such as boron trifluoride, titanium chloride, tin chloride and yttrium triflate, in a solvent which does not participate in the reaction for a reaction time of from 0.5 to 72 hours, preferably from 2 to 24 hours at a reaction temperature of from xe2x88x9278xc2x0 C. to 100xc2x0 C., preferably from xe2x88x9230xc2x0 C. to 60xc2x0 C., and then performing deprotection at need. The compound of formula (I) can be synthesized according to the method of synthetic method (I).
Synthetic Method (IV) 
[In the scheme, R1, R2, R3, and A have the same meanings as those defined above, and Z represents hydrogen atom.]
A compound of formula (VII) can be synthesized by the method shown in the aforementioned synthesis method (I).
The reaction of the compound of formula (VII) and a compound of formula (XII) can be carried out according to the method described in Bioorg. Med. Chem. Lett., 1257(1996), J. Med. Chem., 1652(1989), J. Am. Chem. Soc., 297(1991), Tetrahedron, 3375(1998), Tetrahedron Lett., 2933(1990), U.S. Pat. No. 357,941 or the like. Specifically, the method comprises activating or esterifying the compound of formula (VII), if desired, by using a silyl group or the like to elevate the reactivity of the compound of formula (VII), and subjecting the compound of formula (XII) to Michael addition in a solvent which does not participate in the reaction or without solvent, for a reaction time of from 0.5 to 72 hours, preferably from 2 to 24 hours at a reaction temperature of from xe2x88x9278xc2x0 C. to 100xc2x0 C., preferably from 0xc2x0 C. to 50xc2x0 C. The compound wherein X is xe2x80x94CH2xe2x80x94 and E is hydrogen atom in formula (I) can be synthesized through deprotection at need after the Michael addition.
A compound of formula (XII) can be synthesized according to the method described in J. Med. Chem., 2461(1994) or the like.
Synthetic Method (V) 
[In the scheme, R1, R2, R3, and A have the same meanings as those defined above, and Z represents hydrogen atom.]
A compound of formula (XIII) can be synthesized according to the method shown in the aforementioned synthetic method (IV).
The condensation between the compound of formula (V) and the compound of formula (XIII) can be performed according to the method shown in the aforementioned synthetic method (I), and the compound wherein X is xe2x80x94CH2xe2x80x94 and E is hydrogen atom in formula (I) can be synthesized through deprotection at need after the condensation.
Synthetic Method (VI) 
[In the scheme, R1, R2, R3, and A have the same meanings as those defined above, E represents hydrogen atom or xe2x80x94CH2CH2xe2x80x94 that forms piperidine ring group or a N-substituted piperidine ring group together with A, and Z represents hydrogen atom.]
The compound of formula (VII) can be synthesized by the method shown in the aforementioned synthetic method (I).
A compound of formula (XVI) can be synthesized according to the method described in J. Med. Chem., 2461(1994) or the like.
The condensation between the compound of formula (VII) and the compound of formula (XVI) can be performed according to the method described in Bioorg. Med. Chem. Lett., 1629(1996). Specifically, the compound wherein X is carbon atom in formula (I) can be synthesized by activating the hydroxyl group in formula (XVI) with trifluoromethanesulfonic anhydride, methanesulfonyl chloride, toluenesulfonyl chloride or the like, or substituting the hydroxyl group in formula (XVI) with a halogen atom by a conventional method, and by activating or esterifying the compound of formula (VII) with silyl group or the like at need to elevate the reactivity of the compound of formula (VII), and then, carrying out the reaction in a solvent which does not participate in the reaction or without solvent, in the presence of base at need such as triethylamine, diisopropylethylamine, pyridine, lutidine, potassium carbonate, sodium hydrogencarbonate, sodium hydride and lithium diisopropylamide, for a reaction time of from 0.5 to 72 hours, preferably from 2 to 24 hours at a reaction temperature of from xe2x88x9278xc2x0 C. to 100xc2x0 C., preferably from xe2x88x9278xc2x0 C. to 60xc2x0 C., and performing deprotection at need.
Synthetic Method (VII) 
[In the scheme, R1, R2, R3, and A have the same meanings as those defined above, E represents hydrogen atom or xe2x80x94CH2CH2xe2x80x94 that forms piperidine ring group or a N-substituted piperidine ring group together with A, and Z represents hydrogen atom.]
A compound of formula (XVII) can be synthesized according to the method shown in the aforementioned synthetic method (VI). The condensation between the compound of formula (V) and the compound of formula (XVII) can be performed according to the method shown in the aforementioned synthetic method (I), and the compound wherein X is xe2x80x94CH2xe2x80x94 in formula (I) can be synthesized through deprotection after the condensation.
Specific preparations of the compound of the present invention encompassed within formula (I) are shown in Examples of the specification. Those of ordinary skill in the art can easily prepare the compound of the present invention falling within formula (I) by referring to the aforementioned general explanation and specific explanation in examples, and by appropriately selecting a starting material, a reagent, reaction conditions and the like, and if necessary, applying appropriate modifications and alterations to these methods.
The compound of formula (I) according to the present invention may exist as a salt, and may preferably exist as a pharmacologically acceptable salt. Such salts include medicinally acceptable nontoxic salts, for example, alkali metal salts and alkaline-earth metal salts such as sodium salt, potassium salt, and calcium salt, hydrogen halide salts such as hydrochloride, inorganic salts such as nitrate, sulfate and phosphate, salts of sulfonic acids such as methanesulfonic acid and benzenesulfonic acid, salts of organic acids such as fumaric acid, succinic acid, citric acid, oxalic acid and maleic acid, salts of amino acids such as glutamic acid and aspartic acid, and the like.
The compound of formula (I) according to the present invention may exist as a hydrate or a solvate. Preferred solvates include a solvate with ethanol and the like. Any salts, hydrates, and solvates of the compound of formula (I) fall within the scope of the present invention.
The compound of formula (I) according to the present invention have thrombolytic activity based on inhibition of carboxypeptidase B in human plasma. Accordingly, a substance selected from the group consisting of the compound of formula (I) according to the present invention and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof is useful as an active ingredient of medicaments for therapeutic and/or preventive treatment of various thrombotic diseases such as myocardial infarction, cerebral infarction, angina, pulmonary embolus, chronic arterial obliteration, acute arterial thrombus and embolus, angitis syndrome, diabetic gangrene, thrombophlebitis and deep vein thrombosis, thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome, disseminated intravascular coagulation, and anti-phospholipid antibody syndrome, and pathologic conditions such as diabetes, hyperlipemia, and inflammation in which thrombotic tendency due to the decrease of in vivo fibrinoliablity have been recognized.
The substance selected from the group consisting of the compound of formula (I) according to the present invent ion and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof is also effective as a carboxypeptidase B inhibitor. As the carboxypeptidase B inhibitor according to the present invention, the aforementioned substance, per se, can be used. For example, the inhibitor can also be used as a reagent for enzymes.
The substance selected from the group consisting of the compound of formula (I) according to the present invention and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof, per se, may be used as a medicament. However, the medicament of the present invention is preferably provided as a pharmaceutical composition which comprises the aforementioned substance together with a pharmacologically acceptable carrier, and can be administered to a human as well as an animal other than human by either an oral or parenteral (e go, intravenous, intramuscular, subcutaneous, rectal, transdermal and the like) administration. Two or more of the aforementioned substances may be formulated in combination in the pharmaceutical composition.
The pharmaceutical composition which comprises as an active ingredient a substance selected from the group consisting of the compound of formula (I) according to the present invention and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof can be prepared as a formulation suitable for a route of administration. Specifically, the pharmaceutical composition can be prepared typically in any one of formulations including preparations for parenteral administration such as injections for intravenous or intramuscular administration, drip infusions, inhalants, transdermal preparations, transmucosal preparations, rectal preparations, oleaginous suppositories, and aqueous suppositories, and preparations for oral administration such as capsules, tablets, granules, powders, pills, fine granules, and troches.
As the pharmacologically acceptable carrier used for the manufacture of these various preparations, one or more solid or liquid carriers suitable for administration to humans as well as animals other than humans can be used. Examples of the solid carriers include, for example, starch, lactose, crystalline cellulose, calcium carbonate and the like. Examples of the liquid carriers include, for example, physiological saline, ethanol and the like.
One or more kinds of commonly used excipients, bulking agents, binders, moisturizing agents, disintegrators, surface active agents, lubricants, dispersants, buffering agents, preservatives, solubilizing aids, antiseptics, corrigents, soothing agents, stabilizers and the like may be used as the pharmacologically acceptable carrier. Examples of usable nontoxic carriers include, for example, lactose, fructose, glucose, starch, gelatin, magnesium carbonate, synthetic magnesium silicate, talc, magnesium stearate, methylcellulose and its salts arabic, polyethylene glycol, syrup, Vaseline, ethanol, propylene glycol, citric acid, sodium chloride, sodium sulfite, sodium phosphate and the like.
The content of the substance selected from the group consisting of the compound of formula (I) according to the present invention and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof contained in the pharmaceutical composition may vary depending on dosage forms. Generally, the amount may be from about 1% to about 70% by weight, preferably from about 5% to about 50% by weight based on the total weight of the composition.
A dose can be appropriately chosen in view of the use of the medicament, the age, sexuality and conditions of a patient and the like. The dose may generally be from about 0.1 mg to 1,000 mg, and preferably from 1 mg to 300 mg per day for an adult for therapeutic treatment of thrombotic diseases. The aforementioned dose can be administered once a day or several times a day as divided portions.